There are over 2 million breast cancer survivors today. Persistent cancer-related fatigue (PCRF), a state of being tired or weary, is one of the most common and distressing symptoms experienced by breast cancer (BC) survivors. Rates of significant PCRF in BC survivors range from 30% to 82% within the first 5- years of diagnosis. PCRF is associated with decreased quality of life, decreased sleep quality and depression. Also, subjective reports of low levels of fatigue at diagnosis in BC survivors predict longer recurrence-free (risk ratio [RR] 1.32, 95% confidence interval [CI] 1.13-1.54) and overall survival (RR 1.23, 95%CI 1.05-1.44). Consequently, decreasing PCRF could have a positive impact on women's quality of life and on survival. There are few treatment options for PCRF and these treatments require the availability of a trained practitioner, are associated with significant costs, pose a sizeable burden for the patient, or have unacceptable side-effects. Acupressure is a technique derived from acupuncture, a component of Traditional Chinese Medicine. In acupressure, physical pressure is applied to acupuncture points by the hand, elbow, or with various devices to treat disease. Pilot studies have demonstrated that self-administered acupressure can significantly decrease PCRF by as much as 70% in cancer survivors. Acupressure can also have positive effects on sleep quality in cancer patients and other chronically ill populations. We have performed a pilot clinical trial of acupressure in PCRF. In that trial we observed differential effects of two acupressure formulas, relaxation and stimulatory acupressure, both of which reduced PCRF, with relaxation having a significantly greater effect. Self-administered acupressure is a non-toxic and inexpensive treatment that requires minimal instruction. Acupressure also requires little effort and time on the part of the patient to successfully complete. Thus, acupressure appears to be a promising treatment for PCRF and associated symptoms. As such, we propose a single-blind, placebo controlled study to examine the specific effect of two opposing acupressure treatments compared to standard of care. This study would be conducted in 375 BC survivors at least 12 months after completion of cancer treatments, with moderate to severe PCRF, who will be randomized to one of 3 groups: (1) relaxation acupressure [RA]; stimulating acupressure [SA]; or standard of care for 6-weeks followed by a 4-week washout period. Our primary aim is to examine the effect of 6-weeks of RA compared to SA or standard of care on fatigue as assessed by: (1) weekly self-report using the Brief Fatigue Inventory; (2) objective daytime physical activity on actigraph; or (3) fatigue patterns assessed 4-times daily using a visual analog scale. Secondary endpoints include the examination of the two acupressure regimes or standard of care on sleep quality, and on important kinetic parameters required for implementation of acupressure in a clinical setting; mainly the time to onset for effects of acupressure on fatigue and sleep during the 6-week treatment period and the duration of effect of RA and SA during the 4-week washout period. PUBLIC HEALTH RELEVANCE: There are over 2 million breast cancer survivors today and persistent cancer-related fatigue (PCRF), a state of being tired or weary, is one of the most common and distressing symptoms experienced by breast cancer (BC) survivors. This study will examine a low cost and safe treatment derived from Traditional Chinese Medicine, self- administered acupressure, to treat fatigue in BC survivors. Decreasing fatigue in these women has the ability to improve their quality of life and possibly delay or prevent BC recurrence.